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research overview
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Invasive fungal infections caused by species of Aspergillus, Candida, and Cryptococcus contribute to significant morbidity and mortality in immunocompromised patients. Our laboratory’s research is focused on the human fungal pathogen, Aspergillus fumigatus, that causes deadly Invasive Aspergillosis (IA) disease in immunocompromised patients. The mortality rate for IA is rising due to emerging resistance to guideline-recommended treatments using the azoles and echinocandins. While the growing immunocompromised patient population has outpaced antifungal development, the increasing incidence of antifungal resistance is further hampering effective treatment. As a result, there is a greater and an urgent need for innovative approaches to exploring broad, new antifungal targets with novel mechanisms of action. To design effective antifungal therapeutics a fundamental understanding of fungal growth and pathogenesis mechanisms is necessary.
Our laboratory research is primarily directed toward identifying genes that are indispensable for fungal growth, drug response, and virulence by utilizing a variety of molecular strategies including genetic, biochemical, proteomic techniques and animal models of infection. Over the last 15 years our laboratory research has demonstrated the importance of calcineurin (CN) a calmodulin-dependent protein phosphatase for fungal growth and drug resistance. Our broader whole CN proteomic and phosphoproteomic approaches uncovered several cell wall- and cell membrane-related proteins as potential CN effectors. We also defined unique changes in the A. fumigatus CN proteome in direct response to azole and echinocandin antifungals. Our first fungal CN ternary complex crystal structure-guided inhibitor strategies showed that targeting CN was effective in animal models.
Our overall goal is to elucidate the molecular mechanisms controlling fungal growth, pathogenesis, and drug resistance which will ultimately enable us to identify fungal-specific targets to help design potentially more effective strategies to combat IA.
Ongoing Research:
• Calcineurin regulatory network control of Aspergillus fumigatus hyphal growth.
• Calcineurin role in Aspergillus fumigatus antifungal response and resistance mechanisms.
• Structural approaches to design novel fungal-specific calcineurin inhibitors.
• Protein Kinase A control over Aspergillus fumigatus autophagy and pathogenesis mechanisms.
Impact: Antifungal drug resistance is rapidly emerging and crippling therapeutic options for IA. Novel approaches to deciphering antifungal resistance pathways are urgently needed. Our studies will provide mechanistic understanding of how the CN network drives antifungal response and resistance in A. fumigatus, generating substantial future translational potential for improved strategies to combat invasive fungal disease.
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